A Vitamin D receptor/SMAD Genomic Circuit Gates Hepatic Fibrotic Response

Cell. 2013 Apr 25;153(3):601-13. doi: 10.1016/j.cell.2013.03.028.

Abstract

Liver fibrosis is a reversible wound-healing response involving TGFβ1/SMAD activation of hepatic stellate cells (HSCs). It results from excessive deposition of extracellular matrix components and can lead to impairment of liver function. Here, we show that vitamin D receptor (VDR) ligands inhibit HSC activation by TGFβ1 and abrogate liver fibrosis, whereas Vdr knockout mice spontaneously develop hepatic fibrosis. Mechanistically, we show that TGFβ1 signaling causes a redistribution of genome-wide VDR-binding sites (VDR cistrome) in HSCs and facilitates VDR binding at SMAD3 profibrotic target genes via TGFβ1-dependent chromatin remodeling. In the presence of VDR ligands, VDR binding to the coregulated genes reduces SMAD3 occupancy at these sites, inhibiting fibrosis. These results reveal an intersecting VDR/SMAD genomic circuit that regulates hepatic fibrogenesis and define a role for VDR as an endocrine checkpoint to modulate the wound-healing response in liver. Furthermore, the findings suggest VDR ligands as a potential therapy for liver fibrosis.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Calcitriol / analogs & derivatives
  • Fibrosis / prevention & control
  • Gene Regulatory Networks*
  • Genome-Wide Association Study
  • Hepatic Stellate Cells
  • Liver / injuries
  • Liver / metabolism*
  • Liver / pathology*
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Rats
  • Receptors, Calcitriol / agonists
  • Receptors, Calcitriol / metabolism*
  • Signal Transduction*
  • Smad3 Protein / metabolism
  • Transcriptome
  • Transforming Growth Factor beta1 / metabolism

Substances

  • Receptors, Calcitriol
  • Smad3 Protein
  • Smad3 protein, mouse
  • Transforming Growth Factor beta1
  • calcipotriene
  • Calcitriol

Associated data

  • GEO/GSE41580